Current treatments for chronic pain are often inadequate, require prolonged application, and can lead to dependence and addiction. In particular, there is a pressing need for site-specific non-opioid treatments for neuropathic pain associated with inflammation. The proposed project for the first time introduces theranostic nanomedicine to treatment of pain with aim to reduce or eliminate need for opioid analgesia post-injury. Our long-term goal is to apply novel nanotechnology (theranostics) to help improve patient outcomes by reducing pain and limiting drug-seeking behavior and addiction. Although well established as NSAIDS, COX-2 inhibitors are limited by poor efficacy on neuropathic pain, likely due to poor bioavailability and inability to reach injured nerves in sufficient doses. Furthermore, a major gap exists in our understanding of the site-specific actions of COX-2 inhibitors in the context of neuropathic pain and our ability to direct inhibitors to the site of ijury. Specifically we aim to determine the extent to which a nanoparticle-delivered cyclooxygenase-2 (COX- 2)-inhibitor directed at injury infiltrating activated macrophages will lead to decreases in post-injury pain and need for opioid treatment. This proposal directly addresses two key criteria for the C.E.B.R.A. program: 1) We are testing a completely new hypothesis by testing whether reducing activation of post-injury infiltrating macrophages at the site of a nerve injury will redue pain-like behavior in animals. 2) We are introducing a completely novel technology to pain research by using imaging-supported targeted nanoparticle drug delivery. Specifically, we will apply a theranostic (therapeutic and diagnostic) strategy to simultaneously image and treat pain-inducing inflammation and monitor post-treatment changes in live animals. In this proposal we aim to investigate effects of macrophage targeted theranostic nanoparticles on spontaneous pain and opioid use in chronic constriction injured (CCI) animals. Based on these results and our joint expertise in pain biology and pharmaceutical sciences, we propose the following hypothesis: Inhibition of COX-2 in infiltrating macrophages with theranostic nanoparticles will reduce pain-like behavior and need for opioid analgesia in rats with CCI. This hypothesis will be tested by the following specific aims: Specific Aim 1: Synthesize new theranostic nanoparticles for macrophage-targeted anti-inflammatory action and test their pharmacological effects in vitro. Specific Aim 2: Determine the extent that macrophage targeted theranostic nanoparticles will show efficacy in an animal model of neuropathic pain and reduce need for opioid analgesia. The proposed project, if successful, will: 1) introduce theranostics as novel strategies for studying pain in animal models; and 2) lead to new therapeutic interventions, where macrophage-targeted drug delivery increases efficacy of known anti-inflammatory drugs in treating neuropathic pain leading to reduced use of opioids in post-injury analgesia.